Drug discovery and development

Drug discovery and developmentObjectives of next 5 lectures: you will:be aware of why/how new drugs are

discoveredknow the processes involved in drug

discovery and developmentsee where

pharmacologists/bioscientists may contribute

know about the difficulties and dangers inherent in the drug development process.

What costs what in Leeds? (GPs; 98/99)Omeprazole (anti-gastric acid) £3.5mSimvastatin (cholesterol lowering) £2.4mBeclomethasone (asthma) £1.8mFluoxetine (antidepressant) £1.5mLansoprazole (anti-gastric acid) £1.4mRanitidine (anti-gastric acid) £1.3mParoxetine (antidepressant) £1.2mTOP 7 TOTAL >£13mTotal GP drugs for Leeds >£67m

Why are new drugs needed?

unmet medical need; new diseases (BSE; AIDS, Alzheimer’s; obesity); low efficacy (dementia, cancer); side effects (antidepressants, antipsychotics)

downstream health costs; (Alzheimer’s; spinal injury)

cost of therapy; (Viagra, Interleukins)costs to individual/country; (depression)sustain industrial activity; pharmaceutical

industry employs thousands and makes a massive contribution to overseas earnings); patent expiry

The changed context of drug discovery and development The 1800s: natural sources; limited

possibilities; prepared by individuals; small scale; not purified, standardised or tested; limited administration; no controls; no idea of mechanisms.

The 1990s: synthetic source; unlimited possibilities; prepared by companies; massive scale; highly purified, standardised and tested; world-wide administration; tight legislative control; mechanisms partly understood.

Sources of drugs

Animal insulin (pig, cow)

growth hormone (man) (Creutzfeldt-Jakob)

Plant digitalis (digitalis purpurea - foxglove)

morphine (papaver somniferum)

Inorganic arsenic mercury lithium

Synthetic chemical (propranolol)

biological (penicillin) biotechnology (human insulin)

Drug discovery/development process

discovery; refinement; chemical & biological characterisation

safety & toxicity in animals; formulation development

volunteer studies; patient studiesregulatory process

marketingpost registrationmonitoring

lessons&development

Discovery=find new active structure : Development=convert it to a useful drug

Approaches to drug discoveryHistorical; cinchona (quinine) & willow barks (aspirin);

chinese medicine currently.

Study disease process; breast cancer (tamoxifen); Parkinson’s disease (L-dopa)

Study biochem/physiological pathway; renin/angiotensin

Develop SAR to natural compound; beta-adrenoceptors (propranolol), H2-receptors (cimetidine)

Design to fit known structurally identified biological site; angiotensin-converting enzyme inhibitors

By chance (serendipidy); random screening (HTS); penicillin; dimenhydramate; pethidine

Genomics; identification of receptors; gene therapy; recombinant materials;

DRIVER IS UNMET MEDICAL NEED IN A VIABLE MARKET

Refinement of compounds

Can it be improved? selectivity; duration; route of administration; stability, isomers, ease of preparation.

Can it be patented? costs £250m; takes 8-14 years; high risk business.

USE iterative approach

Levels of testing

DRUG + receptorBINDING

+ transductionsystem (secondmessenger; enzyme)

BIOCHEMICAL TESTING

functionalwhole orpart organs

ISOLATED TISSUE EXPERIMENTS

Anaesthetised or conscious animals

WHOLE ANIMAL EXPERIMENTS

Existing normal behaviours/effects (anaesthesia; contraception; paralysis)

Create behaviours (fat rats; hypertensive rats; anxious rats; epileptic rats)

Find unrelated behaviour affected by existing drugs (Straub tail for narcotic analgesics; learned helplessness for antidepressants)

How predictive is the model?exact replica = 100% predictormechanism same = good predictormechanisms different = poor predictor

Animal models of efficacy

Animal modelspredictive for efficacy AND toxicity?expensive; time consuming; variable;

uncertain; troublesome; ethical questions; skilled workers

legislative control Animal (Scientific Procedures) Act (1986) PERSONAL LICENCE - competent, trained,

procedures specifiedPROJECT LICENCE - allows a personal licence

holder to carry out specified procedures for a specified project that cannot be done without animals and where severity justifies likely gain.

GET INTO MAN EARLY

Reducing animal usage

About 2.6m animals/y used in procedures in UK (11.6m in Europe)

Likely to increase; more research, more targets, genetic capability

3Rs -- 3Rs -- 3RsREPLACEMENT: use non-animal tests if possible

(cheaper, less trouble, less variable but not possible for everything at this time)

REDUCTION: get the statistics right, don’t replicate work unnecessarily, don’t overbreed

REFINEMENT: reduce suffering and severity of procedure, pay attention to housing, stress, husbandry and rich environments, proper analgesia and pre- and post- operative care

Chemical and biological characterisationCHEMICAL; structure, synthesis, purity,

isomers, pKa, stability, solubility, salts, assay

BIOLOGICAL; acute pharmacological profile - LD50, ED50, binding data for many receptors, dose-effect relationships, open field tests, particular tests for different activities (e.g. CVS, CNS, GI tract)

Both positive and negative information is useful.

Acute toxicity profileChronic toxicity profile-- 14 day toxicity test in one rodent and one

non-rodent species before use in man.-- 3 month study read out at 28 days-- longer studies (12 & 24 month)Three dose levels (below, about, well above

human dose).It is insufficient to to use doses which are

not toxic; the doses producing toxic effects and the nature of these effects MUST be established.

Safety & toxicity in animals

Formulation studiesDRUG +Additive: filler, lubricant, coating,

stabiliser, colour, binder, disintegratorDosage form: capsule, tablet, injection,

other?Manipulate duration/profile: e.g.

sustained release

BioequivalenceBioavailabilityEase of use

Clinical testing

{Phase 0 (non-clinical)}Phase 1 (volunteers)Phase 2 (patients)Phase 3 (large scale multi-centre)Phase 4 (post registration monitoring)

phases can also be defined by the information you are trying to get out of the testing

Volunteer studies (phase I trials)

pharmacologists & employees (15-30 in number)

ethical approvalhealthyinformed consentfull rescussitation + medical backupmonitorsingle and repeat dosesincrease dose levels

Volunteer studies (phase I trials)OBJECTIVESmetabolic and excretory pathways

(impinges on toxicity testing in animals)

variability between individuals; effect of route; bioavailability

tolerated dose rangeindication of therapeutic effectsindication of side effects

Patient studies (phase 2 trials)150-350 ill people; informed consentneeds licencemaximum monitoring; full rescussitationoften patients where other treatment

failedOBJECTIVES:indication for use; type of patient; severity

of disease;dose range, schedule and increment;pharmacokinetic studies in ill people;nature of side effects and severity;effects in special groups.

Patient studies (phase 3 trials)1500-3500 ill patientsmulticentre?more certain data for the objectives of

phase 2 studiesinteractions between drugs start to

become measurable in the larger population

sub-groups start to be established special features and problems show up

Clinical trialsDrug action depends on:pharmacodynamicspharmacokinetics and dose regimendrug interactionsreceptor sensitivity of patientmood/personality of patient & doctorpatients expectations and past experiencesocial environment of patientclinical state of patientClinical trial controls these variables and

examines action of drug in defined set of circumstances

The Regulatory process

differs from country to countrydemands safety and quality of productencourages efficacy and need for productgrants clinical trials certificate if volunteer

and animal data OKapproves protocols and examines data50-400 volumes (30,000-150,000 pages)original data availabletwo way process; authority and company

trying to produce a safe effective productrelease for a specific purpose and use

Marketinggetting the product right (packaging;

formulation)right therapeutic slotinformation on new druginformation for honest comparisonreporting problemsreporting new indicationstherapeutic trends

Post-registration monitoring

YELLOW CARD SYSTEM: voluntary reporting of adverse effects by GP to Committee on Safety of Medicines; easy; effective?

INTENSIVE MONITORING OF DEFINED GROUP: first 10,000; administrative nightmare as patients move/die; costly; time-consuming.

RESTRICTED RELEASE: only available to small group of GPs; monitor their patients; elitist

MONITOR INCIDENCE OF DISEASE PROBLEM: difficult to identify cause of change.

Lessons and development

refine parts of treatment giving problems (dose interval? side effects? effective? niche market?)

extend usageeg. PROPRANOLOL (beta adrenoceptor blocker)antidysrhythmic >>> antianginal >>>

antihypertensive >>> relieve hyperthyroid symptoms >>> antihypertensive with diuretic >>> prolonged release formulation

precipitate asthma attack > beta1 selective - ATENOLOL

The future?3rd world diseases?orphan drugs with few users?improve safety and efficacy recordsreduce animal utilisation (cell lines;

early human volunteers, )new diseases (AIDS; Alzheimer’s; CJ

disease;human BSE variant; obesity; cancer)

new biology - (clone human receptors; disease model by gene changes)

patent times and increasing cost

Me-too drugs

Similar to drugs already on marketparallel co-incident developmentnot identical - differences emerge with

timeallergy to one onlyunsuspected side effect causes

discontinuationparticular indication in sub-group of

patientssometimes too many